The outcome of hepatitis B virus (HBV) infection results from complicated interplays among a variety of virus-host interactions. Although host responses likely play a major role, this process is often predicated on a variety of viral adaptive mechanisms. Frequently, viral mutations in critical regions of viral genome are the results of these adaptive mechanisms. Our laboratory has identified and characterized specific viral mutations associated with variant biological behaviors of some HBV strains. Two mutations in the HBV core promotor were identified in a HBV strain associated with fulminant hepatitis leading to highly enhanced replication as a result of increased viral encapsidation of pregenomic RNA into the core particles. Our data suggest that naturally occurring mutations affecting a novel genetic element may influence viral encapsidation by a co- or post-transcriptional mechanism resulting in enhanced core expression and viral replication. Studies are under way to study the clinical significance of these mutations in fulminant or severe hepatitis B. Additional studies are also being initiated to examine other viral mutants including immune escape and drug resistant mutants. The latter aspect is particularly important and relevant in light of increasing clinical use of antiviral compounds that are targeted to viral-encoded functions. Defining the molecular basis of variant manifestations of liver disease associated with infection by naturally occurring HBV mutants may contribute to further understanding of the pathogenesis of HBV infection.